Human IL33 is an interleukin-1-like cytokine of the IL-1 family that signals via the IL-1 receptor-related IL33 receptor (synonyms of the receptor: IL1RL1, T1/ST2) and induces T helper type 2-associated cytokines. Synonyms of IL33 (Swiss-Prot Acc. No. O95760) are interleukin-1 family member 11 (IL-1F11) and nuclear factor from high endothelial venules (NF-HEV). NF-HEV is described in Baekkevold, E. S., et al., Am. J. Pathol. 163 (2003) 69-79. IL33 is described by Schmitz, J., et al., Immunity 23 (2005) 479-490.
Human IL33 Receptor, IL33R, (synonym for ILRL1; SwissProt Acc No. Q01638, other names are ST2, T1/ST2, Fit-1 and DER4) is induced by growth stimulation in fibroblastic cells, and can also be induced by antigen stimulation in Th2 cells. According to the invention IL33R and ST2 denotes human IL33R. Tominaga, S., et al., (FEBS Lett. 258 (1989) 301-304; Biochim. Biophys. Acta. 1171 (1992) 215-218) and Yanagisawa, K., (FEBS Lett. 318 (1993) 83-87) identified human ST2 (the secreted form), ST2L (the transmembrane receptor form) and ST2V (variant Glu-78). Human ST2 is only expressed in growth-stimulated BALB/c-3T3 cells and a member of the primary response gene family induced by growth factors. ST2 encodes a protein similar in sequence to the extracellular portion of human interleukin 1 receptor, both types 1 and 2. Studies with IL33R knockout mice suggest that IL33R is involved in early events of Th2-response (Kropf, P., et al., Infect. Immunity 70 (2002) 5512-5520; Hoshino, K., et al., J. Exp. Med. 190 (1999) 1541-1548; Senn, et al., Eur. J. Immunol. 30 (2000) 1929-1938; Townsend, M. J., et al., J. Exp. Med. 191 (2000) 1069-1076). ST2 is assumed to be a marker, activator and regulator of Th2 immunity (Kumar, R. K., et al., Clin. Exp. Allergy 32 (2002) 1394-1396).
Anti-IL33R antibodies and their role in immune function were described in a number of publications. Anti-human ST2 antibody Mab523 and polyclonal antibody AF523 are commercially availably from R&D Systems (which can be found on the world wide web with a URL address of rndsystems.com). Anti-human ST2 antibody HB12 is commercially availably from antibodies-online GmbH, Germany and MBL Int. Corp. (which can be found on the world wide web with a URL address of mblintl.com). Anti-IL33R antibodies resulted in decreased Th2-type immune responses. The antibody inhibited eosinophil infiltration, IL-5 production, and IgE-production. The evaluation of the role of ST2 in animal models for asthma resulted in increased expression of murine IL33R on CD4+ T cells, indicating a role for IL33R in allergic or asthmatic responses (Löhning, M., et al., Proc. Natl. Acad. Sci. USA 95 (1998) 6930-6935 and Xu, D., et al., J. Exp. Med. 187 (1998) 787-794; Coyle, A. J., et al., J. Exp. Med. 190 (1999) 895-902). Meisel, C., et al., J. Immunol. 166 (2001) 3143-3150 investigate the regulation and function of T1/ST2 expression on CD4+ T cells and the induction of type 2 cytokine production by T1/ST2 cross-linking. Löhning, M., et al., generate an anti-mouse ST2 antibody in rats. Pretreatment with 20 μg (approx 0.0.8 mg/kg) of such an antibody 1 hr before allergen provocation reduced the number of eosinophils in the mouse airway by 70%. Kumar, S., et al., (Biochem. Biophys. Res. Comm. 235 (1997) 474-478 and J. Biol. Chem. 270 (1995) 27905-27913) describe the expression of ST2 protein detected by immunoprecipitation using a rabbit polyclonal antibody generated against purified soluble ST2 receptor expressed in Drosophila. Studies with BALB/c mice revealed that treating with anti-IL33 antibody induced higher Th1-type response. An ELISA system to quantify human ST2 protein in sera of patients was described by Kuroiwa, K., et al., Hybridoma 19 (2000) 151-159. Anti-IL33R antibodies also reduce effects due to infections with RSV (Walzl, et al., J. Exp. Med. 193 (2001) 785-792). Anti-IL33R antibodies were also investigated in an animal model of arthritis (Leung, B. P., et al., J. Immunol. 173 (2004) 145-150; Walzl, et al., J. Exp. Med. 193 (2001) 785-792). Smithgall, M. D., et al., Int. Immunol. 20 (2008) 1019-1030 investigated interferon γ levels in NK cells in the presence of an anti-huST2 antibody. IL33R and/or antibodies against IL33R are mentioned in WO 2005/079844, U.S. Pat. No. 7,087,396, WO 2001/021641, WO 2002/038794, WO 2003/094856. Oboki, K., et al., Allergology Int. 59 (2010) 143-160, review the role of IL33 and IL33 receptors in host defense and diseases and the effects of anti-ST2 antibody, soluble ST2 and anti-IL33 antibody on mouse airway inflammation.